Implantable materials and devices, such as drug delivery systems, pacemakers, artificial joints, and organs play an important role in health care today. In addition to these devices, implantable monitoring devices implantable sensors have great potential for improving both the quality of care and quality of life of patients and animals. Potentially these sensors can measure a wide variety of analytes in the blood and tissue, which would be critical in the early diagnosis and treatment of disease.
Unfortunately the development of these implantable sensors has been hampered by the inability of currently designed implantable sensors to overcome their loss of function and short lifespan in vivo. Frequently this loss of function is a result of the acute and chronic tissue reactions to the implanted sensors. These tissue reactions are a result of various factors including 1) tissue injury and inflammation as a result of tissue trauma from the surgical implantation of the device, 2) immune and non-immune inflammation at the implantation site as a result of “foreign body” reactions to the device, 3) the release to tissue of toxic factors from the function of the device and or the chemical breakdown of the device and its coating. Ultimately, these chronic inflammatory reactions at sites of sensor implantation result in tissue destruction and fibrosis and complete loss of sensor function in vivo.
Conventionally, efforts to extend the in vivo lifespan of implantable glucose sensors have focused on the uses of various sensor coatings, in an effort to “hide or stealth” the sensor from detection and the resulting tissue reactions. Unfortunately these approaches have not been successful, and the use of various coatings has seen limited success because of the body innate and acquired host defense systems (immunity) that can detect minute differences between normal tissue elements and foreign materials such as sensor coatings.
Alternative conventional efforts to incorporate bioactive drugs and peptides and proteins into the coatings or sensor associated drug delivery systems have seen some success. However, in the case of sensor coatings it has been found that 1) frequently only “analyte permeable coatings” can be used as sensor coatings, thus limiting the type of coating available for implantable sensors; 2) binding of sufficient quantities of bioactive agents such as peptides and proteins, can be difficult and often they do not remain active after being bound to the sensor coating; 3) the intense tissue reactions (proteins and cells) frequently “mask” or degrade the bioactive agents on the coatings and limit their effectiveness 4) because of the limited quantities of bioactive agents that can be incorporated into sensor coatings, the coating and therefore the sensor have a limited lifespan in vivo and must be replaced frequently. Additionally the device and its byproducts can also damage both the tissue and the sensor and its coatings. For example, implantable sensors generally function based on the use of glucose oxidase which is specific for glucose. The enzyme needs to be immobilized on the platinum wire by using a carrier protein such as albumin and toxic crosslinking agent such as glutaraldehyde. Additionally, the glucose oxidase used in the sensor continuously breaks down glucose into gluconic acid and hydrogen peroxide, both of which are tissue toxic as well as potentially “sensor toxic”. The hydrogen peroxide is further broken down in reactive oxygen radicals, which are also toxic.
In the case of traditional drug delivery systems such as micro beads, they frequently do not incorporate (load) and or release bioactive agents in quantities and for durations that are useful for implantable sensors. Since the drug delivery system used with implantable sensors are usually located near the sensor, “foreign body” tissue reactions to the drug delivery system often have negative “bystander” effects on the sensor and its function. For example, the breakdown of the drug delivery systems such as micro beads result in the release of tissue toxic and sensor toxic byproducts that hinder sensor function in vivo. Ultimately the combination of inflammation, fibrosis and loss of blood vessels also decrease tissue levels of both glucose and oxygen, both essential to glucose sensor function in vivo, with a resulting loss of sensor function and lifespan in vivo. Clearly in the future, new approaches, methods and devices are needed to extend the function and lifespan of implantable sensors such as the glucose sensors used in conjunction with, for example, the disease condition known as diabetes.
Diabetes is a chronic disease that afflicts over 18 million people in United States, with an annual cost of $132 billion in direct and indirect expenditures in the United States. Diabetes is a leading contributor to many other diseases, including heart disease, stroke, blindness, kidney failure, and peripheral neuropathy. The key factor in preventing these devastating complications of diabetes is the close monitoring of blood glucose levels. Currently, repeated “finger sticks” to obtain capillary blood samples is the major approach to monitoring blood glucose levels. Unfortunately, because of the pain and inconvenience of this procedure associated with “finger sticking” the patient compliance is often poor. However, even with good patient compliance with regular blood glucose testing, it appears that blood glucose swings often stay undetected. For example, initial continuous glucose monitoring has shown that glucose concentrations are only within a target range of 4-10 mmol/l for about 35 percent of the time. Clearly, there is a critical need for a method that would allow continuous blood glucose monitoring in vivo.
Although implantable glucose sensors have been in existence for over 30 years, and in vitro studies have demonstrated that they can function for weeks to months, glucose sensor function in vivo has seen little success. Previous in vivo studies have indicated that implantable glucose sensors lose function within hours to days after implantation.
It is generally accepted that the loss of sensor function in vivo is associated with sensor induced tissue injury, inflammation and fibrosis with associated blood vessel regression. Presently there has been little progress in the developments for the reason described above. In fact currently available glucose sensors display rapid loss in sensor function within 1-3 days post sensor implantation, and even these sensors require frequent reference “finger sticks” to determine blood glucose levels to utilize to recalibrate the implanted sensor. Clearly a new approach and devices are needed for enhancing the in vivo function and lifespan of implanted sensors such as the glucose sensor.